Amyotrophic lateral sclerosis (ALS) is a degenerative disease of motor neurons that inexorably leads to progressive weakness and death. The incidence of ALS is significantly increased among veterans of foreign wars, and thus it has a major impact on veteran health care. Sadly, the pathophysiology of this disease remains largely a mystery, and there are no effective treatments. In recent work from our laboratory, we have identified dysregulation of growth factor mRNA stability and translation as a novel mechanistic direction to understanding the basis for ALS. Mutations of Cu, Zn superoxide dismutase (SOD)1 that are associated with familial ALS gain a high RNA binding affinity for U- and AU-rich elements present in 5' and 3' untranslated regions (UTR) of many critical growth and cytoprotective factors. Through an interaction with cellular RNA binding proteins (RBP), these elements govern stability and translation of the transcript and provide an important pathway for rapid upregulation of survival factors during cellular stress. The RBP, HuR, plays a major positive role in this molecular pathway by binding to these elements. We previously showed that mutant SOD1, through its gain of high RNA binding affinity, disrupts HuR stabilization and translation of vascular endothelial growth factor mRNA, a critical neuroprotective factor for motor neurons. We found that apoptosis and mitochondrial dysfunction in cells expressing mutant SOD1 could be reversed by upregulating HuR. Based on this work, we hypothesize here that upregulation of HuR can rescue motor neuron degeneration induced by mutant SOD1 by reversing aberrant post-transcriptional processing of survival factor mRNAs in motor neurons directly or by enhanced VEGF production of surrounding astrocytes. We have the animal cellular models necessary to test this exciting possibility. This work has the real potential to establish a foundation for developing novel therapeutic approaches to this devastating disease. Specific Aims: 1. To determine whether HuR can rescue the cytotoxic phenotype of mutant SOD1 in motor neurons and astrocytes using in vitro and in vivo mouse models. 2. To determine the molecular impact of transgenic HuR expression in motor neurons and astrocytes with regard to posttranscriptional regulation and production of cytoprotective factors. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis is a relentless disease of motor neurons that leads to progressive paralysis of the muscles and ultimately death. There is a significantly increased incidence of this disease in our veterans of foreign wars, and there is no cure or mitigating therapy. This proposal will address a novel area of growth factor regulation that may contribute to the cause of this disease, and thus may ultimately lead to novel therapies.